Systemic AAV8-Mediated Gene Therapy Drives Whole-Body Correction of Myotubular Myopathy in Dogs
Systemic AAV8-Mediated Gene Therapy Drives Whole-Body Correction of Myotubular Myopathy in Dogs
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DOI：
10.1016/j.ymthe.2017.02.004
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发表时间：
2017-04-05
影响因子：
12.4
通讯作者：
Childers, Martin K.
中科院分区：
文献类型：
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作者：
Mack, David L.;Poulard, Karine;Childers, Martin K.
X连锁肌管性肌病（XLMTM）由MTM 1基因突变和肌管蛋白缺乏引起。大多数XLMTM患者通常在2岁内出现严重的肌无力，导致呼吸衰竭和死亡。我们的目的是通过进行剂量递增研究来评估全身基因治疗在XLMTM p.N155K犬模型中的有效性和安全性。将在肌肉特异性结蛋白启动子下表达犬肌微管蛋白（cMTM 1）的重组腺相关病毒血清型8（rAAV 8）载体（rAAV 8-cMTM 1）通过简单外周静脉输注给予10周龄时已出现疾病体征的XLM TM犬。在为期9个月的研究期间，对生存率、肢体力量、步态、呼吸功能、神经评估、组织学、载体生物分布、转基因表达和免疫应答进行了综合分析。结果表明，全身性基因治疗耐受性良好，寿命延长，并以剂量依赖性方式纠正全身骨骼肌肉组织，定义了该疾病的大型动物模型中的有效剂量。这些结果支持XLMTM基因治疗临床试验的发展。
X-linked myotubular myopathy (XLMTM) results from MTM1 gene mutations and myotubularin deficiency. Most XLMTM patients develop severe muscle weakness leading to respiratory failure and death, typically within 2 years of age. Our objective was to evaluate the efficacy and safety of systemic gene therapy in the p.N155K canine model of XLMTM by performing a dose escalation study. A recombinant adeno-associated virus serotype 8 (rAAV8) vector expressing canine myotubularin (cMTM1) under the muscle-speCific desmin promoter (rAAV8-cMTM1) was administered by simple peripheral venous infusion in XLMTM dogs at 10 weeks of age, when signs of the disease are already present. A comprehensive analysis of survival, limb strength, gait, respiratory function, neurological assessment, histology, vector biodistribution, transgene expression, and immune response was performed over a 9-month study period. Results indicate that systemic gene therapy was well tolerated, prolonged lifespan, and corrected the skeletal musculature throughout the body in a dose-dependent manner, defining an efficacious dose in this large-animal model of the disease. These results support the development of gene therapy clinical trials for XLMTM.